tbuckley/cabot-search huggingface dataset:
Abstract 1871: Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors
Authors: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Christina Wheeler, Matthew Lucas, Charles Xing, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short
Journal: Cancer Research (2023)

Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers and is associated with poor prognosis. Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies, therapeutic benefit is limited by many resistance mechanisms and toxicities. Clinical trials of therapeutics redirecting T cell activity to HER2+ tumors have highlighted the apparent risk of on-target, off-tumor adverse effects for this target, as HER2 is also expressed in normal epithelia. Using BioAtla’s Conditionally Active Biologic (CAB) platform, we have developed a HER2 x CAB-CD3 bispecific antibody that was engineered to bind with high affinity to the CD3 receptor and induce T cell activation under conditions that mimic the tumor microenvironment, but with reduced binding in physiological conditions. Both in vitro and in vivo efficacy data for a CAB T cell engager (TCE) targeting HER2 will be presented. Our data will demonstrate that HER2 x CAB-CD3 bispecific antibody promotes cytotoxicity of HER2+ cancer cells in vitro and induces complete regression of tumor growth in vivo. The HER2 x CAB-CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. The generation of CAB bispecific antibodies with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling higher potency-TCEs for targeting drug resistant, low expressing-HER2+ tumors. In summary, the use of CAB technology expands the universe of targets for drug development by generating a new class of potent CAB T-cell engagers with increased safety margin for potentially enhanced therapeutic indices in the clinic. Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Christina Wheeler, Matthew Lucas, Charles Xing, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1871.
Abstract 872: Deciphering the activation mechanism of CDK4/cyclin-D complex that differs from the CDK2/cyclin-E complex
Authors: Wengang Zhang, Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2023)

Abstract Cyclin-dependent protein kinases (CDKs) regulate the eukaryotic cell cycle progression. Dysregulated cell cycle leading to unscheduled cell proliferation is a characteristic of many cancer subtypes. Since some tumor cells require specific interphase CDKs for proliferation, understanding CDKs activation mechanisms and their differential recognition of cognate cyclins and substrate proteins are essential for developing selective CDK inhibitors for cancer treatments. To date, while the crystal structure of the active CDK2 in complex with cyclin-E is available, no crystal structure for active CDK4 with its cognate cyclin-D is resolved. Here, we model the CDK4/cyclin-D complex as well as CDK2 in complex with cyclin-E to study the conformational dynamics and activation processes of G1 and G1/S phases CDKs, respectively. Extensive molecular dynamics (MD) simulations were performed for both CDK complexes with the kinases in different transition states to resolve the differences in their allosteric regulations at the atomic level. We illustrate that the inactive CDK4 in complex with cyclin-D is in the intermediate state on its pathway to activation in contrast to the fully active CDK2 in complex with cyclin-E, suggesting its activation mechanism is distinct from that of CDK2. This suggests that additional steps such as ATP binding, extension of the activation loop (A-loop), rotation of αC-helix towards “IN” conformation, phosphorylation of A-loop, and substrate binding are required for CDK4. CDK2 interacts with cyclin-E through a large interfacial area (or interface) that stabilizes the protein-protein interaction, while CDK4 has a smaller interfacial area (or interface) in the interaction with cyclin-D. Our simulations affirm experimental data on the current understanding of activation mechanisms of CDK2 and CDK4 and reveal additional atomistical characteristics of their dynamics and activations. Our works report the complete activation mechanisms of CDK2/4, providing insights into the inhibition of these complexes at an atomic level, and are useful for identifying potential targets for drug discovery in oncology. Citation Format: Wengang Zhang, Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. Deciphering the activation mechanism of CDK4/cyclin-D complex that differs from the CDK2/cyclin-E complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 872.
Abstract 1870: VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers
Authors: Oi Kwan Wong, Xinhua Wang, Xiaocheng Chen, Leonard Post
Journal: Cancer Research (2023)

Abstract CD47/SIRPα axis is an important checkpoint of innate immune system and is often exploited by tumor cells to evade host immune surveillance. In recent years, therapies such as anti-CD47 monoclonal antibodies (mAbs) and SIRPα fusion proteins that target this axis have garnered much attention. Although exciting clinical activities have been observed in hematological cancers, responses in solid tumors are less impressive and often require complex combination strategies. We previously described a novel CD47xEpCAM bispecific antibody, VBI-003, built on a human IgG1 backbone to harness the power of blocking CD47/SIRPα pathway while preserving the effector functions of IgG1 Fc (J ImmunoTher Cancer 2021;9:doi: 10.1136/jitc-2021-SITC2021.274). The bispecific design aims to improve selectivity so that SIRPα blocking and stable binding occur selectively on tumor cells where both CD47 and EpCAM are present. In vitro studies show that VBI-003 exhibits minimal red blood cell binding and does not cause hemagglutination, in contrast to benchmark CD47 mAb. VBI-003 has potent single agent activity in cell line derived xenograft (CDX) models of gastric and esophageal cancers. Here, we further explored the anti-tumor activities of VBI-003 in areas with great unmet needs such as small cell lung cancers (SCLC) and colorectal cancers (CRC). Gene expression analysis from public datasets reveals frequent expression of CD47 and EpCAM in SCLC and CRC tumors. Flow cytometry studies confirmed co-expression of CD47 and EpCAM on SCLC and CRC cell lines. Furthermore, in vitro assays showed that VBI-003 has potent EpCAM dependent SIRPα blocking, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity activities towards SCLC and CRC cell lines. Moreover, VBI-003 demonstrated potent single agent activity in multiple CDX models of SCLC with tumor regression and often outperformed benchmark CD47 mAb. Significant tumor growth inhibition was observed in colorectal cancer models post VBI-003 treatment, with additional activity by combination with standard of care chemotherapies. VBI-003 synergized with irinotecan and outperformed monotherapy groups in CDX models of CRC. In conclusion, VBI-003 has potent single agent activity in SCLC tumor models and combined synergistically with irinotecan in CRC models. Our data support further investigation of VBI-003 as a treatment for CD47 and EpCAM expressing SCLC and CRC. Citation Format: Oi Kwan Wong, Xinhua Wang, Xiaocheng Chen, Leonard Post. VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1870.
Abstract 1730: A novel chimeric virus-like drug conjugate (VDC) for the potential treatment of HPV-positive tumors
Authors: Rhonda C. Kines, Anneli Savinainen, Elisabet de los Pinos, John T. Schiller
Journal: Cancer Research (2023)

Abstract Introduction: Human papillomavirus (HPV) virus-like particles (VLPs) bind to a wide variety of tumor types via modified glycosaminoglycans (GAGs) found on the tumor cell surface. This finding led to the development of the investigational virus-like drug conjugate (VDC) belzupacap sarotalocan (bel-sar, formerly AU-011), an HPV-derived VLP conjugated to a light-activated cytotoxic payload. When activated by near-infrared light, bel-sar induced rapid tumor necrosis resulting in pro-immunogenic cell death, release of tumor neoantigens and long-term anti-tumor immunity in the TC-1 tumor model. When E6 and E7 expressing TC-1 mouse tumors were treated with the VDC, E7-specific T-cells were detected in the absence of provided tumor antigens. A novel chimeric VDC (cVDC) is now in development, in which E6 and E7 are fused to the L2 capsid protein as a means to potentially further enhance the observed anti-tumor response. This cVDC could allow for the targeted cytotoxicity of HPV-positive tumors in addition to the release of supplemental tumor antigens E6 and E7 within the now pro-immunogenic tumor milieu, potentially leading to a long term anti-tumor response. Methods: The detoxified sequences of E6 and E7 were engineered as one fusion polypeptide on the C-terminus of the L2 minor capsid protein. Both L2/E6/E7 and L2/E7/E6 protein expression vectors were generated to determine if the order of the proteins impacted L2’s ability to co-assemble with L1, the major capsid protein. The plasmids were co-expressed alongside L1 using the mammalian 293TT expression system. Results: Both the L2/E6/E7 and L2/E7/E7 fusion proteins were expressed and co-assembled with L1 into chimeric VLPs. Fusion protein expression was validated by western blots for L2, E6 and E7, and VLPs were confirmed by electron microscopy. Conclusions: Preliminary data indicate that chimeric VDCs containing E6 and E7 can successfully be generated using the 293TT mammalian expression system. Studies evaluating the cytotoxicity and E6 and E7 immunogenicity of the cVDC as well as the impact on tumor targeting are underway. Citation Format: Rhonda C. Kines, Anneli Savinainen, Elisabet de los Pinos, John T. Schiller. A novel chimeric virus-like drug conjugate (VDC) for the potential treatment of HPV-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1730.
Abstract 1064: Cancer-specific molecular subtypes of pancreatic cancer reveal clinically relevant molecular dependency
Authors: Sung Hwan Lee, Jiyeon Park, Sunyoung Lee, Ju-Seog Lee
Journal: Cancer Research (2023)

Abstract Introduction: Pancreatic cancer is lethal, showing dismal prognosis and therapeutic resistance. Previous molecular subtypes from genome or transcriptome did not show clinical relevance regarding precision strategy for optimal therapeutic options followed by precise patient classification. This study aims to uncover consensus molecular subtypes from cancer-specific multi-omics data showing clinically relevant therapeutic opportunities. Methods: We performed comprehensive analyses using the dataset from the cancer dependency map (DepMap) project, including cancer-specific molecular characterization with multi-omics data, genome-wide loss-of-function screening using the CRISPR-Cas9 system, and cancer drug sensitivity. The subtype-specific molecular signatures were validated in independent translational cohorts (TCGA-PAAD; n=150, ICGC-PACA-AU; n=461, ICGC-PACA-CA; n=317). Results: Integrative profiling of multi-omics molecular layers (Mutational signature, Copy number alteration, Transcriptome, MicroRNA, Chromatic profile, Proteome, and Metabolome) from pancreatic cancer cell lines (n=59) from the Cancer Cell Line Encyclopedia (CCLE) revealed a total of three cancer-specific molecular subtypes showing distinct tumor biology through all omics layer as well as clinical relevance with unique molecular dependency. Major molecular features of each subtype were reproducible in the validation cohorts. Subtype-specific molecular biomarkers, including mutational signatures and metabolites, were identified. Finally, the target drug with subtype-specific genetic dependency was analyzed to provide a precision strategy according to distinct subtypes’ molecular characterization. Conclusions: Integrative profiling from multi-omics molecular layers revealed precision strategies based on cancer-specific molecular subtypes of pancreatic cancer in terms of tumor classification and discriminative therapeutic opportunities. Prospective translational studies companion with clinical trials based on cancer-specific molecular subtypes is mandatory to establish the precision strategy for managing pancreatic cancer. Citation Format: Sung Hwan Lee, Jiyeon Park, Sunyoung Lee, Ju-Seog Lee. Cancer-specific molecular subtypes of pancreatic cancer reveal clinically relevant molecular dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1064.
Abstract 1281: Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC
Authors: Ana G. Ayala Pazzi, Omar Karkoutly, Kristopher Ezell, Samantha Lopez, Kyle D. Doxtater, Elias George, Vijian Dhevan, Manish K. Tripathi
Journal: Cancer Research (2023)

Abstract The Y-Box Binding protein 1 (YB-1) is a 324 amino acid-long member of the Cold Shock Domain (CSD) protein superfamily. YB-1 interacts with micro RNAs and non-coding RNAs in the cytoplasm, acting as a regulator of mRNA translation. YB-1 translocation into the nucleus is circadian clock-dependent and leads to the upregulation of cyclin gene expression, among others. Another mechanism of nuclear translocation of YB-1 is mediated by phosphorylation of the Ser 102 residue in the CSD. The YB-1 oncoprotein acts as a transcription factor when bound to DNA, modulating the transcription of genes that regulate biological processes such as Multidrug Resistance Mutation 1 (MDR1). YB-1 is linked to poor prognosis in breast, prostate, and liver cancer. Despite advances in biomedicine, the incidence and mortality of hepatocellular carcinoma (HCC) remain high. Sorafenib, a tyrosine kinase Inhibitor (TKI), is the first-line treatment for advanced HCC. Sorafenib also inhibits downstream activation of NF-kB by inhibition of Lyn phosphorylation (Y397). However, it was observed in many patients that its sorafenib’s effectiveness is hampered by drug resistance, but the mechanism is still unclear. We have found that SK-HEP-1 HCC cells transfected with a YB-X-1 overexpression plasmid subsequently developed into a stable YB-1 overexpression cell line (SK-HEP-1+YB-1) displayed increased invasion, migration, proliferation, and colony formation property as compared to the vector control (SKHEP1+Vec). The SK-HEP-1+YB-1 cell line also showed increased IC50 for sorafenib and elevated phosphorylation of Lyn (Y397) and further activated NF-kB (S165/S176) phosphorylation. This indicates YB-1 may cause increased Sorafenib resistance in HCC by activating tyrosine kinases (TK), such as lyn, and simultaneous activation of NF-kB. The combination of YB-1 inhibition and sorafenib might provide a novel therapeutic strategy and improve the survival of patients with advanced-stage HCC. Citation Format: Ana G. Ayala Pazzi, Omar Karkoutly, Kristopher Ezell, Samantha Lopez, Kyle D. Doxtater, Elias George, Vijian Dhevan, Manish K. Tripathi. Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1281.
Abstract 1011: Hsa_circ_0116796 as a novel biomarker for predicting prognosis of human hepatocellular carcinoma
Authors: Huiwon Do, Gyeonghwa Kim, Yu Rim Lee, Won Young Tak, Soo Young Park, Keun Hur
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. It lacks sufficient diagnostic and prognostic markers, which leads to a poor prognosis. The survival rate of HCC patients is still low due to its highly metastatic nature. According to recent studies, non-coding RNAs play a vital role in cancer pathogenesis and may be a new diagnostic target for HCC. Circular RNA (circRNA) is a type of non-coding RNA with a closed loop structure formed by mRNA back-splicing. Its functions are miRNA sponging, translating to proteins and gene regulation. Recently, it has been found that circRNAs play a potential role at angiogenesis, metastasis, and drug resistance in many types of cancers. Thus, we aim to investigate the clinical relevance of hsa_circ_0116796 in HCC.Total RNAs from 100 pairs of HCC and corresponding normal liver (NL) tissues with different stages were extracted using QIAzol. CircRNA primers were coded including the gap junction for specificity. The expression levels were determined by quantitative real-time PCR (qRT-PCR), and its expression was normalized with GAPDH. In addition, we analyzed the correlation between hsa_circ_0116796 expression and various clinicopathological features of HCC patients. The target miRNAs were predicted in silico analyses. We found that hsa_circ_0116796 was significantly decreased in HCC tumor tissues compared to corresponding NL tissues (P&amp;lt;0.001). Suppression of hsa_circ_0116796 expression was associated with HCC progression (P&amp;lt;0.001). Moreover, hsa_circ_0116796 expression was significantly associated with T-stage (P=0.009), TNM stage (P=0.005), BCLC stage (P=0.0132), and survival (P&amp;lt;0.001). We provided the novel evidence for usefulness of hsa_circ_0116796 expressions as strong potential biomarkers for diagnosis and predicting prognosis of HCC patients. Citation Format: Huiwon Do, Gyeonghwa Kim, Yu Rim Lee, Won Young Tak, Soo Young Park, Keun Hur. Hsa_circ_0116796 as a novel biomarker for predicting prognosis of human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1011.
Abstract 1047: Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group
Authors: Klara Cervena
Journal: Cancer Research (2023)

Abstract Pancreatic cancer (PANC) has among solid malignancies one of the lowest 5-years survival rates - less than 10%. To improve the prognosis of PANC, it is necessary to develop tools that will enable earlier diagnosis. More than 90% of PANC cases are characterized by the presence of KRAS mutations in tumor tissue that play a critical role in the initiation of PANC. Recently, attention has been focused on liquid biopsy which can better reflect the whole genetic profile of the tumor and may enable early diagnosis. Our study aims to discover whether KRAS gene mutations can be detected in the plasma isolated from the PANC risk group patients - diabetes mellitus II (DMII) and chronic pancreatitis (CP). The KRAS mutations were analyzed in 34 PANC, 89 DMII, and 31 CP patients by droplet digital PCR. Plasma cell-free DNA was investigated for three mutations hotspots: KRAS p.G12D c.35G&amp;gt;A, p.G12V c.35G&amp;gt;T, p.G12R. Detailed results of the study are currently under evaluation and will be presented during the meeting. We believe that these results discover whether plasma analysis of KRAS mutation can serve as a biomarker for early diagnosis of malignant transformation in risk group patients. Supported by grant AZV NU-21-07-00247, by Czech science Foundation 22-05942S and by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102). Citation Format: Klara Cervena. Plasma KRAS mutations as predictive biomarkers for pancreatic cancer in high-risk group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1047.
Abstract 1673: Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors
Authors: Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Joonwoo Nam, Jaewoo Park, Keon Wook Kang, Wooseok Han
Journal: Cancer Research (2023)

Abstract Molecular glue degraders (MGDs) of neo-substrates that function by hijacking the CRBN E3 ligase are clinically validated as therapeutics for the treatment of hematological malignancies. Novel MGDs of GSPT1, a translation termination factor, elicit dysregulated protein translation termination and subsequent induction of TP53-independent apoptosis in acute myeloid leukemia (AML) cells through activation of the integrated stress response. In addition, dysregulation of translation termination triggered by GSPT1 degradation appears to be cytotoxic specifically to MYC-driven cancers including solid tumors with translational addiction. Phase 1 clinical trials of three novel GSPT1 MGDs have been recently launched for the treatment of AML and/or MYC-driven solid tumors (NCT02848001, NCT04336982, NCT05546268, and NCT05144334). Herein, we present novel GSPT1 MGDs and their pre-clinical results against AML and solid tumors. Our current lead GSPT1 MGDs induced rapid, potent, and durable degradation of GSPT1, resulting in strong inhibition of tumor cell growth in a variety of cell lines of MYC-driven solid tumor and blood cancer (AML and acute lymphoblastic leukemia). Moreover, in ex-vivo assays using a panel of patient-derived primary AML cells, C-10386 was highly sensitive with EC50s at the nanomolar range. Furthermore, a related analogue (C-14207) showed excellent rodent PK profiles and demonstrated dose-dependent PKPD relationship and excellent efficacy in the NCI-H1155 NSCLC xenograft model. Finally, our current lead compounds showed safer profiles in various normal cells compared to other known GSPT1 degraders. Collectively, we have identified novel GSPT1 MGDs as promising development candidates for the treatment of AML and solid tumors. Citation Format: Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Joonwoo Nam, Jaewoo Park, Keon Wook Kang, Wooseok Han. Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1673.